This proposal describes a five-year mentored physician-scientist training program to define the contribution of long non-coding RNAs in cardiovascular disease. Disturbances in cholesterol homeostasis are major contributors to cardiovascular disease and associated comorbidities. The liver X receptors (LXRs) is central regulators of sterol homeostasis. Activation of LXRs promotes reverse cholesterol transport/excretion and limits cholesterol uptake/absorption. The administration of LXR agonists has potent atheroprotective effects and reverses established disease; hence LXR agonists have generated strong interest as therapeutic targets. The actions of LXRs are opposed by Sterol Regulatory Element-binding Protein 2 (SREBP-2), the master regulator of cholesterol biosynthesis. Although prior studies have implicated microRNAs in lipoprotein metabolism, the contribution of other non-coding RNAs to lipid homeostasis and atherosclerosis remain unexplored. A unique group of non-coding RNAs known as large intergenic non-coding (linc) RNAs exhibit moderate evolutionary conservation and participate in diverse biologic processes with direct links to human diseases. Utilizing next-generation sequencing technology we identified a lincRNA that we named LeXis (Liver-expressed LXR-induced sequence) as a novel LXR target gene. The objective of this project is to define the function of LeXis in physiology and metabolism. My preliminary studies suggest that LeXis regulates serum cholesterol levels in vivo via feedback repression of SREBP-2 and cholesterol biosynthesis. I hypothesize that LeXis plays a role in cholesterol homeostasis through tissue-specific modulation of SREBP-2 transcription. I propose a series of molecular, cell biological, and animal studies to extend my preliminary observations and test my hypothesis. Targeting SREBP-2 in a context-specific manner may lower serum cholesterol while minimizing off target effects. Not only will our proposed work provide fundamental insights into how lncRNAs work, but may also open a new frontier for drug development, since it is conceivable that LeXis mimetic oligonucleotides might be used as therapeutic drugs. Thus, the proposed work is of high translational potential. The outlined program will allow the candidate to develop the skills and tools needed to embark upon this research project, while having the necessary mentorship and support needed towards the goal of maturing into an independent investigator. The aims of this project are aligned with the major strategic goal of NHLBI to improve our understanding of the molecular and physiologic basis of health and disease.